Hydroxyurea Therapy May Affect Fertility in Sickle Cell Disease

A systematic review and meta-analysis suggested the use of hydroxyurea therapy can impact fertility rates, including seminal fluid parameters and ovarian reserves, for men and women with sickle cell disease (SCD).¹

These analyses point to the need for education on common infertility risk factors, alongside disease- and treatment-associated fertility risks, in patients with SCD, indicating its importance given the lack of risk differences based on sex.

“Based on this finding, it is the opinion of the authors that fertility preservation counseling should be considered in patients with SCD in both genders of reproductive age, prior to hydroxyurea therapy,” wrote the investigative team, led by Abdulrahman Alsultan, MBBS, Oncology Center, King Saud University Medical City.¹

Current statistics estimate the global birth rate of SCD is 515,000 individuals per year or 382 cases per 100,000 live births.² Hydroxyurea is widely available and clinically effective for treating SCD—initially recommended for adults with clinical complications, patients as young as 9 months old are recommended hydroxyurea irrespective of disease severity.³

However, concerns about the long-term of hydroxyurea continue to persist, particularly for fertility, as evidence has documented adverse effects on sperm counts in male patients and diminished ovarian reserves in female patients.^4,5 Exposure to hydroxyurea in children could thus compromise fertility and reproductive capability from an early age.

A systematic literature review was performed to identify articles published from inception to July 2023 in the PubMed and EMBASE databases, focusing on primary fertility outcomes, stratified by male or female sex.¹ Participants were aged ≥6 years, had the hemoglobin SS genotype of SCD, and received hydroxyurea therapy.

Outcomes were measured based on the frequency of events. Male-based studies evaluated the effect of hydroxyurea on the volume of ejaculate, spermatozoa concentration, total sperm count, spermatozoa morphology, and vitality. Female-focused studies measured the effect of hydroxyurea on anti-Müllerian hormone (AMH), normal ovarian reserve, and diminished ovarian reserve.

The review identified a total of 160 potentially relevant articles. Exclusion criteria left the full texts of 34 potentially relevant studies and 8 were finally included for the meta-analysis. These studies included four cohort studies for males encompassing 205 patients and four cohort studies for females including 149 patients.

Upon analysis, pooled data revealed the overall mean difference in the volume of ejaculate among males was not significantly impacted by hydroxyurea therapy (P = .71). In male patients, hydroxyurea therapy also did not considerably affect initial forward motility (P = .33) or spermatozoa morphology (P = .95).

However, hydroxyurea treatment significantly reduced the concentration of spermatozoa (mean difference [MD], –15.48 million/mL [95% CI, –20.69 to –10.26]; P <.001). Spermatozoa concentrations did not recover after treatment cessation (MD, –20.09 million/mL [95% CI, –38.78 to –1.40]; P = .04).

Further analysis demonstrated a significant reduction in the total sperm count during hydroxyurea treatment (MD, –105.87 million [95% CI, –140.61 to –71.13]; P <.001), which did not recover after cessation (MD, –53.05 million [95% CI, –104.96 to –1.14]; P = .05).

For female patients with SCD, these analyses revealed a significantly greater likelihood of low AMH values than age-matched controls (odds ratio [OR], 2.6 [95% CI, 1.1 – 6.5]; P = .02).

In particular, after hydroxyurea treatment, the pooled mean values of AMH were 1.83 (95% CI, 1.42 - 2.56), below the normal range for the mean age of the cohort, suggesting the therapy is associated with reduced AMH levels.

During hydroxyurea therapy, and after treatment, approximately 72.2% of patients showed normal ovarian reserves (95% CI, 42 - 89%). The rest of the population (18.8%) experienced diminished ovarian reserves (95% CI, 11 - 43%), indicating a significant negative impact on fertility in female patients with SCD.

“Increased knowledge of fertility in both males and females following the cessation of hydroxyurea therapy is now urgently required given the limited recovery observed and lack of available data to fully document recovery,” investigators wrote.

References

1. _{Sewaralthahab S, Alsubki LA, Alhrabi MS, Alsultan A. Effects of hydroxyurea on fertility in male and female sickle cell disease patients. A systemic review and meta-analysis. PLoS One. 2024;19(6):e0304241. Published 2024 Jun 7. doi:10.1371/journal.pone.0304241}
2. _{GBD 2021 Sickle Cell Disease Collaborators. Global, regional, and national prevalence and mortality burden of sickle cell disease, 2000-2021: a systematic analysis from the Global Burden of Disease Study 2021 [published correction appears in Lancet Haematol. 2023 Aug;10(8):e574. doi: 10.1016/S2352-3026(23)00215-6]. Lancet Haematol. 2023;10(8):e585-e599. doi:10.1016/S2352-3026(23)00118-7}
3. _{Reeves SL, Jary HK, Gondhi JP, Raphael JL, Lisabeth LD, Dombkowski KJ. Hydroxyurea use among children with sickle cell anemia. Pediatr Blood Cancer. 2019;66(6):e27721. doi:10.1002/pbc.27721}
4. _{Kroner BL, Hankins JS, Pugh N, et al. Pregnancy outcomes with hydroxyurea use in women with sickle cell disease. Am J Hematol. 2022;97(5):603-612. doi:10.1002/ajh.26495}
5. _{DeBaun MR. Hydroxyurea therapy contributes to infertility in adult men with sickle cell disease: a review. Expert Rev Hematol. 2014;7(6):767-773. doi:10.1586/17474086.2014.959922}